This application for continuation of the Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins supports a highly interactive, multidisciplinary, and inter-institutional program. Five research projects within three research themes, four cores, a career development and a research developmental program are proposed to extend our translational research In colorectal and pancreatic cancer. Theme 1: Epidemiology and Inborn risk (Project 1, Markers for risk in familial pancreatic cancer, Drs. Klein, Hruban, and Goggins) Theme 2: Management of risk (Project 2, Markers for screening and diagnosis, Drs. Goggins and Kinzler; Project 3, Diagnostic strategies and risk-assessment for pancreatic cysts, Drs. Kinzler, Maitra, and Goggins). Theme 3: Post-diagnostic management (Project 4, Tumor antigens for individual signatures and therapy, Drs. Jaffee, Kern, and lacobuzio-Donahue; Project 5, Access of therapeutic agents to cancer cells, Drs. Zhou, Kern, and lacobuzio-Donahue). The cores support the research programs (Core 1, Administration and Communication, Dr. Scott Kern; Core 2, Human Tissue Research and Logistics, Dr. Christine lacobuzio-Donahue; Core 3, Familial Cancer Registries, Dr. Frank Giardiello; Core 4, Statistics/Bioinformatics, Drs. Alison Klein. The Career Development Program (Dr. Scott Kern) aids the emergence of new investigators and the Research Developmental Program (Dr. Bert Vogelstein) provides rapid funding of innovative directions.